Brian Shine

Relationship between bacterial strain type, host biomarkers, and mortality in Clostridium difficile infection.

Clostridium difficile genotype predicts 14-day mortality in 1893 enzyme immunoassay–positive/culture-positive adults. Excess mortality correlates with genotype-specific changes in biomarkers, strongly implicating inflammatory pathways as a major influence on poor outcome. Polymerase chain reaction ribotype 078/ST 11(clade 5) is associated with high mortality; ongoing surveillance remains essential.

Effect of bilateral internal mammary artery grafts on long-term survival: a meta-analysis approach.

Background— Although the potential survival benefit of bilateral internal mammary artery (BIMA) grafting in comparison with single internal mammary artery (SIMA) grafting has been emphasized by many investigators, the use of BIMA is still low in clinical practice in the absence of randomized trials and long-term results. In the current study, we aimed to assess if there is a long-term survival benefit of BIMA up to 10 years after coronary bypass surgery. Methods and Results— We selected published articles comparing survival between SIMA and BIMA patients with follow-up duration of more than a mean of 9 years. We evaluated the log hazard ratio with 95% confidence interval for included studies by using a random-effects meta-analysis. Nine eligible observational studies provided 15 583 patients (8270 SIMA and 7313 BIMA) for meta-analysis. Five studies used propensity score methods for statistical adjustment, 2 with a propensity score–based patient-matching method and 3 with quintile-based stratification. A significant reduction in mortality by using BIMA was observed (hazard ratio, 0.79; 95% confidence interval, 0.75–0.84); no study showed any significantly harmful effect of BIMA on survival. Subgroups of studies using different statistical approaches—unmatched, quintile-based propensity score analysis, and propensity score–based exact patient matching—all showed the survival benefit of BIMA grafting. Conclusions— BIMA grafting appears to have better survival with up to 10 years follow-up in comparison with SIMA grafting. Long-term survival benefit of BIMA seems to continue in the second decade after surgery. An ongoing randomized trial comparing SIMA and BIMA groups will add evidence on this issue.

Diabetes as a Determinant of Mortality in Cystic Fibrosis

OBJECTIVE Diabetes is increasingly common in cystic fibrosis, but little information describing its influence on mortality exists. Using national U.K. data, in this study we document diabetes-specific mortality rates, estimate the impact of diabetes on survival, and estimate population-attributable fractions. RESEARCH DESIGN AND METHODS This retrospective cohort study identified 8,029 individuals aged 0–65 years from the U.K. Cystic Fibrosis Registry (1996–2005). A total of 5,892 patients were included in analyses of mortality rates, and 4,234 were included in analyses of risk factors. We calculated age-adjusted mortality rates using Poisson regression, standardized mortality ratios using the population of England and Wales, and relative risks using proportional hazards modeling. RESULTS During 17,672 person-years of follow-up, 393 subjects died. The age-adjusted mortality rate was 1.8 per 100 person-years (95% CI 1.6–2.0). The age-adjusted mortality rates per 100 person-years were 2.0 (1.8–2.4) in female subjects and 1.6 (1.4–1.9) in male subjects, and 4.2 (3.4–5.1) in individuals with diabetes vs. 1.5 (1.3–1.7) in those without diabetes. Independent risk factors for death included diabetes (hazard ratio 1.31 [95% CI 1.03–1.67], female sex (1.71 [1.36–2.14]) plus poorer pulmonary function, lower BMI, Burkholderia cepacia infection, absence of Staphylococcus aureus infection, allergic bronchopulmonary aspergillosis, liver disease, prior organ transplantation, and corticosteroid use. CONCLUSIONS Individuals with cystic fibrosis die earlier if they have diabetes, which, if delayed or better treated, might reasonably extend survival; this hypothesis merits testing.

Long-term effects of lithium on renal, thyroid, and parathyroid function: a retrospective analysis of laboratory data.

BACKGROUND Lithium is a widely used and highly effective treatment for mood disorders, but causes poorly characterised adverse effects in kidney and endocrine systems. We aimed to analyse laboratory information system data to determine the incidence of renal, thyroid, and parathyroid dysfunction associated with lithium use. METHODS In a retrospective analysis of laboratory data from Oxford University Hospitals National Health Service Trust (Oxfordshire, UK), we investigated the incidence of renal, thyroid, and parathyroid dysfunction in patients (aged ≥18 years) who had at least two creatinine, thyrotropin, calcium, glycated haemoglobin, or lithium measurements between Oct 1, 1982, and March 31, 2014, compared with controls who had not had lithium measurements taken. We used survival analysis and Cox regression to estimate the hazard ratio (HR) for each event with lithium use, age, sex, and diabetes as covariates. FINDINGS Adjusting for age, sex, and diabetes, presence of lithium in serum was associated with an increased risk of stage three chronic kidney disease (HR 1·93, 95% CI 1·76-2·12; p<0·0001), hypothyroidism (2·31, 2·05-2·60; p<0·0001), and raised total serum calcium concentration (1·43, 1·21-1·69; p<0·0001), but not with hyperthyroidism (1·22, 0·96-1·55; p=0·1010) or raised adjusted calcium concentration (1·08, 0·88-1·34; p=0·4602). Women were at greater risk of development of renal and thyroid disorders than were men, with younger women at higher risk than older women. The adverse effects occurred early in treatment (HR <1 for length of treatment with lithium). Higher than median lithium concentrations were associated with increased risk of all adverse outcomes. INTERPRETATION Lithium treatment is associated with a decline in renal function, hypothyroidism, and hypercalcaemia. Women younger than 60 years and people with lithium concentrations higher than median are at greatest risk. Because lithium remains a treatment of choice for bipolar disorder, patients need baseline measures of renal, thyroid, and parathyroid function and regular long-term monitoring. FUNDING None.

Multiple endocrine neoplasia type 1 (MEN1) germline mutations in familial isolated primary hyperparathyroidism

background Familial isolated hyperparathyroidism (FIHP) is an autosomal dominant disorder characterized by uniglandular or multiglandular parathyroid tumours that occur in the absence of other endocrine tumours. The disorder may represent either an early stage of multiple endocrine neoplasia type 1 (MEN1), or an allelic variant of MEN1, or a distinct entity involving another locus. We have explored these possibilities in seven families in whom primary hyperparathyroidism occurred as the sole endocrinopathy.

Genetic Determinants and Epidemiology of Cystic Fibrosis–Related Diabetes: Results from a British cohort of children and adults

OBJECTIVE—Longer survival of patients with cystic fibrosis has increased the occurrence of cystic fibrosis–related diabetes (CFRD). In this study we documented the incidence of CFRD and evaluated the association between mutations responsible for cystic fibrosis and incident CFRD, while identifying potential risk factors. RESEARCH DESIGN AND METHODS—This was a population-based longitudinal study of 50 cystic fibrosis speciality clinics in the U.K. Subjects included 8,029 individuals aged 0–64 years enrolled in the U.K. Cystic Fibrosis Registry during 1996–2005. Of these, 5,196 with data and without diabetes were included in analyses of incidence, and 3,275 with complete data were included in analyses of risk factors. Diabetes was defined by physician diagnosis, oral glucose tolerance testing, or treatment with hypoglycemic drugs. RESULTS—A total of 526 individuals developed CFRD over 15,010 person-years. The annual incidence was 3.5%. The incidence was higher in female patients and in patients with mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene in classes I and II. In a multivariate model of 377 cases of 3,275 patients, CFTR class (relative risk 1.70 [95% CI 1.16–2.49], class I or II versus others), increasing age, female sex, worse pulmonary function, liver dysfunction, pancreatic insufficiency, and corticosteroid use were independently associated with incident diabetes. CONCLUSIONS—The incidence of CFRD is high in Britain. CFTR class I and II mutations increase the risk of diabetes independent of other risk factors including pancreatic exocrine dysfunction.

Asymptomatic Children with Multiple Endocrine Neoplasia Type 1 Mutations May Harbor Nonfunctioning Pancreatic Neuroendocrine Tumors

CONTEXT Multiple endocrine neoplasia type 1 (MEN1) is characterized by the occurrence of parathyroid, pituitary, and pancreatic tumors. MEN1, an autosomal dominant disorder, has a high degree of penetrance, such that more than 95% of patients develop clinical manifestations by the fifth decade, although this is lower at approximately 50% by age 20 yr. However, the lower penetrance in the younger group, which is based on detecting hormone-secreting tumors, may be an underestimate because patients may have nonfunctioning tumors and be asymptomatic. OBJECTIVE The aim of the study was to evaluate the occurrence of nonfunctioning pancreatic neuroendocrine tumors in asymptomatic children with MEN1. PATIENTS Twelve asymptomatic Northern European children, aged 6 to 16 yr, who were known to have MEN1 mutations were studied. RESULTS Two asymptomatic children, who were aged 12 and 14 yr, had normal plasma fasting gastrointestinal hormones and were found to have nonfunctioning pancreatic neuroendocrine tumors that were more than 2 cm in size. Surgery and immunostaining revealed that the tumors did not have significant expression of gastrointestinal hormones but did contain chromogranin A and synaptophysin, features consistent with those of nonfunctioning pancreatic neuroendocrine tumors. The tumors had a loss of menin expression. The 14 yr old also had primary hyperparathyroidism and a microprolactinoma, and the 12 yr old had a nonfunctioning pituitary microadenoma. Three other children had primary hyperparathyroidism and a microprolactinoma. CONCLUSION Nonfunctioning pancreatic neuroendocrine tumors may occur in asymptomatic children with MEN1 mutations, and screening for such enteropancreatic tumors in MEN1 children should be considered earlier than the age of 20 yr, as is currently recommended by the international guidelines.

Chronic kidney disease: a large-scale population-based study of the effects of introducing the CKD-EPI formula for eGFR reporting

Objective To evaluate the effects of introducing the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) formula for estimated glomerular filtration rate (eGFR) reporting in the adult population in routine clinical practice with clinician-directed testing. Design Retrospective study of all creatinine measurements and calculation of eGFRs using Modification of Diet in Renal Disease (MDRD) and CKD-EPI formulae. Setting General population, Oxfordshire, UK. Participants An unselected population of around 660 000. Interventions Reporting of eGFRs using MDRD or CKD-EPI formulae. Primary and secondary outcome measures Evaluation of the effects of the CKD-EPI formula on the prevalence of different stages of chronic kidney disease (CKD). Results The CKD-EPI formula reduced the prevalence of CKD (stages 2–5) by 16.4% in patients tested in primary care. At the important stage 2–stage 3 cut-off, there was a relative reduction of 7.5% in the prevalence of CKD stages 3–5 from 15.7% to 14.5%. The CKD-EPI formula reduced the prevalence of CKD stages 3–5 in those aged <70 but increased it at ages >70. Above 70 years, the prevalence of stages 3–5 was similar with both equations for women (around 41.2%) but rose in men from 33.3% to 35.5%. CKD stages 4–5 rose by 15% due exclusively to increases in the over 70s, which could increase specialist referral rates. The CKD classification of 18.3% of all individuals who had a creatinine measurement was altered by a change from the MDRD to the CKD-EPI formula. In the UK population, the classification of up to 3 million patients could be altered, the prevalence of CKD could be reduced by up to 1.9 million and the prevalence of CKD stages 3–5 could fall by around 200 000. Conclusions Introduction of the CKD-EPI formula for eGFR reporting will reduce the prevalence of CKD in a primary care setting with current testing practice but will raise the prevalence in the over 70s age group. This has implications for clinical practice, healthcare policy and current prevalence-based funding arrangements.

Increasing burden of community-acquired pneumonia leading to hospitalisation, 1998-2014.

Background Community-acquired pneumonia (CAP) is a major cause of mortality and morbidity in many countries but few recent large-scale studies have examined trends in its incidence. Methods Incidence of CAP leading to hospitalisation in one UK region (Oxfordshire) was calculated over calendar time using routinely collected diagnostic codes, and modelled using piecewise-linear Poisson regression. Further models considered other related diagnoses, typical administrative outcomes, and blood and microbiology test results at admission to determine whether CAP trends could be explained by changes in case-mix, coding practices or admission procedures. Results CAP increased by 4.2%/year (95% CI 3.6 to 4.8) from 1998 to 2008, and subsequently much faster at 8.8%/year (95% CI 7.8 to 9.7) from 2009 to 2014. Pneumonia-related conditions also increased significantly over this period. Length of stay and 30-day mortality decreased slightly in later years, but the proportions with abnormal neutrophils, urea and C reactive protein (CRP) did not change (p>0.2). The proportion with severely abnormal CRP (>100 mg/L) decreased slightly in later years. Trends were similar in all age groups. Streptococcus pneumoniae was the most common causative organism found; however other organisms, particularly Enterobacteriaceae, increased in incidence over the study period (p<0.001). Conclusions Hospitalisations for CAP have been increasing rapidly in Oxfordshire, particularly since 2008. There is little evidence that this is due only to changes in pneumonia coding, an ageing population or patients with substantially less severe disease being admitted more frequently. Healthcare planning to address potential further increases in admissions and consequent antibiotic prescribing should be a priority.

Hyperglycemia and Death in Cystic Fibrosis–Related Diabetes

OBJECTIVE Diabetes is common in cystic fibrosis and increases the risk of death, yet the role of hyperglycemia remains unproven. An association between glycemia and mortality would provide compelling evidence to support glucose lowering in cystic fibrosis–related diabetes (CFRD). RESEARCH DESIGN AND METHODS Using the U.K. Cystic Fibrosis Registry, we analyzed longitudinal data from 2006 to 2009 in 520 individuals with diabetes. We tested the association between HbA1c and mortality. RESULTS During a median follow-up of 2 years, 36 patients died. The median value of HbA1c was higher in those who died (7.3%) than in those who did not (6.7%). An HbA1c value of ≥6.5% was associated with a threefold increased risk of death (hazard ratio 3.2 [95% CI 1.4–7.3]; P = 0.005) independent of potential confounders. CONCLUSIONS Hyperglycemia trebles the risk of death in patients with CFRD. These findings provide epidemiologic support for continued efforts to improve glycemic control.